Michael Schomaker and colleagues estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies in Southern Africa.
Please see later in the article for the Editors' Summary
There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2–5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2–5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4 percentage (CD4%) <25%.
Methods and Findings
ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping.
The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm3 (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1–6.5) (no ART) to 2.1% (95% CI: 1.3%–3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%–3.5%) and 2.2% (95% CI: 1.4%–3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data.
The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm3 or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values.
Please see later in the article for the Editors' Summary
Infection with HIV, the virus that causes AIDS, contributes substantially to the burden of disease in children. Worldwide, more than 3 million children younger than 15 years old (90% of whom live in sub-Saharan Africa) are HIV-positive, and every year around 330,000 more children are infected with HIV. Children usually acquire HIV from their mother during pregnancy, birth, or breastfeeding. The virus gradually destroys CD4 lymphocytes and other immune system cells, leaving infected children susceptible to other potentially life-threatening infections. HIV infection can be kept in check, with antiretroviral therapy (ART)—cocktails of drugs that have to be taken daily throughout life. ART is very effective in children but is expensive, and despite concerted international efforts over the past decade to provide universal access to ART, in 2011, less than a third of children who needed ART were receiving it.
Why Was This Study Done?
For children diagnosed as HIV-positive between the ages of two and five years, the 2010 World Health Organization (WHO) guidelines for the treatment of HIV infection recommended that ART be initiated when the CD4 count dropped below 750 cells/mm3 blood or when CD4 cells represented less than 25% of the total lymphocyte population (CD4 percent). Since June 2013, however, WHO has recommended that all HIV-positive children in this age group begin ART immediately, irrespective of their CD4 values. Earlier ART initiation might reduce mortality (death) and morbidity (illness), but it could also increase the risk of toxicity and of earlier development of drug resistance. In this causal modeling analysis, the researchers estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies of ART undertaken in southern Africa. Specifically, they compared the estimated mortality associated with the WHO 2010 and WHO 2013 guidelines. Observational studies compare the outcomes of groups (cohorts) with different interventions (here, the timing of ART initiation). Data from such studies are affected by time-dependent confounding: CD4 count, for example, varies with time and is a predictor of both ART initiation and the probability of death. Causal modeling techniques take time-dependent confounding into account and enable the estimation of the causal effect of an intervention on an outcome from observational data.
What Did the Researchers Do and Find?
The researchers used g-computation (a type of causal modeling) adjusting for time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score (a measure of whether a child is underweight for their age that provides a proxy indicator of the clinical stage of HIV infection) to estimate mortality for ART initiation at different CD4 thresholds in 2,934 ART-naïve, HIV-positive children aged 2–5 years old at their first visit to one of eight study sites in southern Africa. The average initial CD4 values of these children were a CD4 count of 592 cells/mm3 and a CD4 percent of 16%. The estimated cumulative mortality after three years was 3.4% in all children if ART was never started. If all children had started ART immediately after diagnosis irrespective of CD4 value or if the 2010 WHO-recommended threshold of a CD4 count below 750 cells/mm3 or a CD4 percent below 25% was followed, the estimated cumulative mortalities after three years were 2.1% and 2.2%, respectively (a statistically non-significant difference).
What Do These Findings Mean?
These findings suggest that, among southern African children aged 2–5 years at HIV diagnosis, there is no difference in mortality for up to three years between children in whom ART is initiated immediately and those in whom ART initiation is deferred until their CD4 value falls below a CD4 count of 750 cells/mm3 or a CD4 percent of 25%. Although causal modeling was used in this analysis, the accuracy of these results may be affected by residual confounding. For example, the researchers were unable to adjust for the clinical stage of HIV disease at HIV diagnosis and instead had to use weight-for-age z-scores as a proxy indicator of disease severity. Other limitations of the study include the large number of children lost to follow-up and a possible lack of generalizability—most of the study participants were from urban settings in South Africa. Importantly, however, these findings suggest that the recent change in the WHO guidelines for ART initiation in young children is unlikely to increase or reduce mortality, with the proviso that the long-term effects of earlier ART initiation such as toxicity and the development of resistance to ART need to be explored further.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001555
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa and on children and HIV/AIDS (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children and its 2013 consolidated guidelines on the use of ART can be downloaded
The researchers involved in this study are part of the International Epidemiologic Databases to Evaluate AIDSSouthern Africa collaboration, which develops and implements methodology to generate the large datasets needed to address high-priority research questions related to HIV/AIDS
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline